This invention relates to compounds and pharmaceutical compositions useful for the treatment anxiety, depression and hypertension. More particularly, this invention concerns certain novel 8-alkoxy-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole, 5-alkoxy-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-c]pyridine, and 9-alkoxy-2,3,3a,4,5,9b-hexahydro-1H-benz[e]isoindole compounds useful in the treatment of anxiety, depression, and hypertension by virtue of their high affinity and selectivity for the 5-HT.sub.1A (5-hydroxytryptamine) subtype of serotonin receptors.
The serotonergic system exerts a complex and as yet not fully understood control over cardiovascular and CNS function. Multiple subtypes of the serotonin receptor have been described; and specific functions have been ascribed to certain of these subtypes which would indicate that pharmacological intervention would produce beneficial therapeutic results.
In particular, the 5-HT.sub.1A subtype of the serotonin receptor has been shown to exert significant control over the cardiovascular function, and may be involved as well in the etiology of anxiety and depression. Activation of centrally located 5-HT.sub.1A receptors has been shown to have an inhibitory effect on sympathetic outflow. Selective agonists of this receptor site have been shown to be efficacious in the treatment of hypertension in experimental animals. Although the precise mechanism of this antihypertensive effect has not been unequivocally determined, the currently available evidence suggests that this response to 5-HT.sub.1A selective agonists is mediated by decreased total peripheral resistance rather than decreased cardiac output. Therefore, modulation of central 5-HT.sub.1A receptors represents a novel and potentially useful method for the control of hypertension not found in any currently available drug.
The use of 5-HT.sub.1A selective agents in the treatment of anxiety has now become a clinically established principle. Again, the precise mechanisms by which these agents exert their anxiolytic effects have not been determined. Modulation of the serotonergic nervous system has become an equally well established principle for the treatment of depression, and current evidence has suggested that 5-HT.sub.1A selective agents may have therapeutic efficacy. Serotonergic abnormalities have been suggested for a variety of additional disease states such as, but not limited to, migraine, schizophrenia, dementia, eating disorders, sexual disorders, and nausea. Serotonic receptor subtype selective agents may find utility in the treatment of such disorders.